Maraviroc and its pharmaceutically acceptable salt or solvate thereof were disclosed in U.S. Pat. No. 6,667,314 (herein after refer to '314 patent). Maraviroc is chemically, N-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo-[3.2.1]oct-8-yl]-1-phenylpropyl}-4,4-difluorocyclohexanecarboxamide and has the structural formula:

Maraviroc as modulators of the chemokine receptor CCR5 and thus useful in the treatment of retroviral diseases caused by viruses that utilize CCR5 to enter cells. In particular maraviroc has been disclosed as being a useful therapeutic in the treatment of HIV, a retroviral infection genetically related to HIV, AIDS, or an inflammatory disease.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, to dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other
Maraviroc or its salts can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
According to the '314 patent, maraviroc can be prepared by reacting a solution of (1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenyl-1-propanamine in methylene chloride and saturated sodium carbonate with a solution of 4,4-difluorocyclohexanecarbonyl chloride in toluene, and isolating to obtain maraviroc.
Crystalline polymorph form A and form B of maraviroc were disclosed in U.S. Pat. No. 7,576,097.
Amorphous form of maraviroc was reported in IP.com Journal (2006), 6(12B), 31. According to this process, amorphous form is obtained from crystalline maraviroc.
Polymorphic forms of maraviroc phosphate are obtained not specifically mentioned in '314 patent. We have discovered novel crystalline forms of maraviroc phosphate.
We have also discovered novel process for the preparation of maraviroc amorphous form. The amorphous form obtained by the process of the present invention is found to have substantially pure as measured by high performance liquid chromatography (HPLC). The process of the invention ensures that amorphous maraviroc can be obtained directly without the need for the preparation of the crystalline maraviroc first, then the conversion of crystalline maraviroc to the maraviroc amorphous form.
Thus, one object of the present invention is to provide a novel crystalline forms of maraviroc phosphate, processes for their preparation and pharmaceutical compositions comprising them.
The crystalline forms of maraviroc phosphate of the present invention may also serve as intermediate for preparation of maraviroc.
Another object of the present invention is to provide a novel process for the preparation of maraviroc amorphous form and pharmaceutical compositions comprising it.